title: Exendin-4 improves β-cell function in autophagy-deficient β-cells.
abstract: Autophagy is cellular machinery for maintenance of β-cell function and mass. The implication of autophagy failure in β-cells on the pathophysiology of type 2 diabetes and its relation to the effect of treatment of diabetes remains elusive. Here, we found increased expression of p62 in islets of db/db mice and patients with type 2 diabetes mellitus. Treatment with exendin-4, a glucagon like peptide-1 receptor agonist, improved glucose tolerance in db/db mice without significant changes in p62 expression in β-cells. Also in β-cell-specific Atg7-deficient mice, exendin-4 efficiently improved blood glucose level and glucose tolerance mainly by enhanced insulin secretion. In addition, we found that exendin-4 reduced apoptotic cell death and increased proliferating cells in the Atg7-deficient islets, and that exendin-4 counteracted thapsigargin-induced cell death of isolated islets augmented by autophagy deficiency. Our results suggest the potential involvement of reduced autophagy in β-cell dysfunction in type 2 diabetes. Without altering the autophagic state in β-cells, exendin-4 improves glucose tolerance associated with autophagy deficiency in β-cells. This is mainly achieved through augmentation of insulin secretion. In addition, exendin-4 prevents apoptosis and increases the proliferation of β-cells associated with autophagy deficiency, also without altering the autophagic machinery in β-cells.
authors.affiliation: or Toyoyoshi Uchida, M.D., Ph.D., Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. hwatada@juntendo.ac.jp or uchitoyo@juntendo.ac.jp.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Abe
authors.forename: Toyoyoshi
authors.initials: T
authors.lastname: Uchida
authors.forename: Akemi
authors.initials: A
authors.lastname: Hara
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mizukami
authors.forename: Koji
authors.initials: K
authors.lastname: Komiya
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.forename: Nayumi
authors.initials: N
authors.lastname: Shigihara
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Toyofuku
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ogihara
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Soroku
authors.initials: S
authors.lastname: Yagihashi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujitani
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Watada
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2; D000077270:Exenatide; D005786:Gene Expression Regulation / Q000502:physiology; D018149:Glucose Intolerance / Q000188:drug therapy; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
chemical_list: C502661:Atg7 protein, mouse; D001786:Blood Glucose; C490981:Gtf2h1 protein, mouse; D008869:Microtubule-Associated Proteins; D010455:Peptides; D014157:Transcription Factors; D014688:Venoms; D051758:Transcription Factor TFIIH; D000077270:Exenatide; D000071193:Autophagy-Related Protein 7